WO2019200202A1 - Antagonistes de l'intégrine humaine (alpha4) (beta7) - Google Patents

Antagonistes de l'intégrine humaine (alpha4) (beta7) Download PDF

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WO2019200202A1
WO2019200202A1 PCT/US2019/027141 US2019027141W WO2019200202A1 WO 2019200202 A1 WO2019200202 A1 WO 2019200202A1 US 2019027141 W US2019027141 W US 2019027141W WO 2019200202 A1 WO2019200202 A1 WO 2019200202A1
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Prior art keywords
compound
methyl
mmol
propanoate
alkyl
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PCT/US2019/027141
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English (en)
Inventor
Matthew G. Bursavich
Dawn M. TROAST
Bryce A. Harrison
Blaise S. LIPPA
Bruce N. Rogers
Kyle D. KONZE
Aleksey I. GERASYUTO
Tyler DAY
Fu-Yang Lin
Kristopher N. HAHN
Mats A. SVENSSON
Byungchan Kim
Cheng Zhong
Alexey A. Lugovskoy
Brian SOSA
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Morphic Therapeutic, Inc.
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Priority to JP2020555323A priority Critical patent/JP7365358B2/ja
Priority to CN201980033206.5A priority patent/CN112312910A/zh
Priority to EP19785592.7A priority patent/EP3773573A4/fr
Publication of WO2019200202A1 publication Critical patent/WO2019200202A1/fr
Priority to JP2023174330A priority patent/JP2024001201A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the heterodimeric integrin family of receptors modulate cellular shape and cell adhesion to the extracellular matrix in response to extrinsic and intrinsic cues.
  • Integrin signaling controls cell survival, cell cycle progression, cell differentiation, and cell migration.
  • the integrin receptor exclusively can signal a cell bi-directionally, both“inside-out” and “outside-in.” Thus, they mediate cell migration by transmitting forces from the extracellular matrix to the cytoskeleton and regulate cytoskeletal organization to achieve shape changes needed during cell migration.
  • Integrins are expressed on the surface of most of human cells. Their pathology contributes to a diverse set of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular degeneration and various autoimmune and chronic inflammation diseases.
  • Integrins form heterodimers of two different chains: the a (alpha) and b (beta) subunits.
  • the a4b7 integrin is expressed on lymphocytes and is responsible for T-cell homing into gut-associated lymphoid tissues through its binding to mucosal addressin cell adhesion molecule (MAdCAM), which is present on high endothelial venules of mucosal lymphoid organs.
  • MAdCAM mucosal addressin cell adhesion molecule
  • Inhibitors of specific integrin-ligand interactions have been shown effective as antiinflammatory agents for the treatment of various autoimmune diseases.
  • monoclonal antibodies displaying high binding affinity for a4b7 have displayed therapeutic benefits for gastrointestinal auto-inflammatory/autoimmune diseases, such as Crohn's disease, and ulcerative colitis.
  • the invention relates to a compound of Formula I:
  • R 1 is H, alkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-O-alkyl, aryl, heteroaryl, or alkylene-CF 3 ;
  • R 2 is heterocyclyl
  • R 4 is H, or (Ci-Ce)-alkyl
  • R a is H, alkyl, cycloalkyl, CN, or -O-alkyl
  • R b is H, aryl, heterocylcyl, -O-cycloalkyl, -O-aryl, or -O-heterocyclyl;
  • R c is H, alkyl, cycloalkyl, hetrocyclyl, or alkylene-CF 3;
  • R d is aryl, heteroaryl, heterocyclyl, -O-cycloalkyl, -O-aryl, or -O-heterocyclyl;
  • R e is aryl, heteroaryl, or heterocyclyl
  • the invention relates to a method of treating a disease or a condition selected from the group consisting of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma and graft versus host disease, chronic inflammatory diseases of the lung, HIV, and hematological tumor, comprising the step of: administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein.
  • Figure 1 is a table summarizing in vitro inhibition of a4b7 integrin by exemplary compounds.
  • the invention relates to compounds that antagonize a4b7 integrin.
  • the compounds will be useful for the treatment of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, graft versus host disease, chronic inflammatory diseases of the lung, HIV, or hematological tumor.
  • a reference to“A and/or B”, when used in conjunction with open-ended language such as“comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • “or” should be understood to have the same meaning as“and/or” as defined above.
  • “or” or“and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as“only one of’ or“exactly one of,” or, when used in the claims,“consisting of,” will refer to the inclusion of exactly one element of a number or list of elements.
  • the phrase“at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase“at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and ⁇ -enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • lactate lactate
  • phosphate, tosylate citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et ah, supra).
  • A“therapeutically effective amount” (or“effective amount”) of a compound with respect to use in treatment refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.
  • prophylactic or therapeutic treatment includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • a patient refers to a mammal in need of a particular treatment.
  • a patient is a primate, canine, feline, or equine.
  • a patient is a human.
  • An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below.
  • a straight aliphatic chain is limited to unbranched carbon chain moieties.
  • the term“aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.
  • Alkyl refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made.
  • alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties.
  • Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer.
  • Alkyl goups may be substituted or unsubstituted.
  • alkylene refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain.
  • alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CLLCLhCLL))-, and the like.
  • Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.
  • Cycloalkyl means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.
  • lower alkyl means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • “lower alkenyl” and “lower alkynyl” have similar chain lengths.
  • preferred alkyl groups are lower alkyls.
  • a substituent designated herein as alkyl is a lower alkyl.
  • Alkenyl refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety.
  • Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).
  • Alkynyl refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur moiety attached thereto.
  • the“alkylthio” moiety is represented by one of -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2)m-R 1 , wherein m and R 1 are defined below.
  • Representative alkylthio groups include methylthio, ethylthio, and the like.
  • alkoxyl or“alkoxy” as used herein refers to an alkyl group, as defined below, having an oxygen moiety attached thereto.
  • alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.
  • An“ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, -O-alkynyl, -0-(CH2)m-Rio, where m and Rio are described below.
  • amine and“amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the formulae:
  • Rn, R12 and R13 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-Rio, or R11 and R12 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rio represents an alkenyl, aryl, cycloalkyl, a cycloalkenyl, a heterocyclyl, or a polycyclyl; and m is zero or an integer in the range of 1 to 8.
  • only one of R11 or R12 can be a carbonyl, e.g., R11, R12, and the nitrogen together do not form an imide.
  • R11 and R12 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- Rio.
  • alkylamine as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R11 and R12 is an alkyl group.
  • an amino group or an alkylamine is basic, meaning it has a conjugate acid with a pK a > 7.00, i.e., the protonated forms of these functional groups have pK a s relative to water above about 7.00.
  • amide refers to a group
  • each RI 4 independently represent a hydrogen or hydrocarbyl group, or two Ri4 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aryl as used herein includes 3- to l2-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl).
  • aryl groups include 5- to l2-membered rings, more preferably 6- to lO-membered rings
  • the term“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • Heteroaryl groups include substituted or unsubstituted aromatic 3- to l2-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to lO-membered rings, whose ring structures include one to four heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.
  • halo means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
  • halo is selected from the group consisting of fluoro, chloro and bromo.
  • heterocyclyl or“heterocyclic group” refer to 3- to l2-membered ring structures, more preferably 5- to l2-membered rings, more preferably 5- to lO-membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfmyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, and the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino,
  • carbonyl is art-recognized and includes such moieties as can be represented by the formula:
  • X’ is a bond or represents an oxygen or a sulfur
  • Ris represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-Rio or a pharmaceutically acceptable salt
  • Ri6 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-Rio, where m and Rio are as defined above.
  • X’ is an oxygen and Ris or Ri6 is not hydrogen
  • the formula represents an“ester.”
  • X’ is an oxygen
  • Ris is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when Ris is a hydrogen, the formula represents a “carboxylic acid”.
  • X’ is an oxygen, and Ri6 is a hydrogen
  • the formula represents a “formate.”
  • the oxygen atom of the above formula is replaced by a sulfur
  • the formula represents a“thiocarbonyl” group.
  • X’ is a sulfur and Ris or Ri6 is not hydrogen
  • the formula represents a“thioester” group.
  • X’ is a sulfur and Ris is a hydrogen
  • the formula represents a“thiocarboxylic acid” group.
  • X’ is a sulfur and Ri6 is a hydrogen
  • the formula represents a“thioformate” group.
  • X’ is a bond, and Ris is not hydrogen
  • the above formula represents a“ketone” group.
  • X’ is a bond, and Ris is a hydrogen
  • the above formula represents an“aldehyde” group.
  • the term“substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term“nitro” means -NO2; the term“halogen” designates -F, -Cl, -Br, or -I; the term“sulfhydryl” means -SH; the term“hydroxyl” means -OH; the term “sulfonyl” means -SO2-; the term“azido” means -N3; the term“cyano” means -CN; the term “isocyanato” means -NCO; the term “thiocyanato” means -SCN; the term “isothiocyanato” means -NCS; and the term“cyanato” means -OCN.
  • R15 is as defined above.
  • sulfonamide is art recognized and includes a moiety that can be represented by the formula:
  • R54 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • R54 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfoxido or“sulfmyl”, as used herein, refers to a moiety that can be represented by the formula
  • Rn is selected from the group consisting of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl
  • urea is art-recognized and may be represented by the general
  • each Ris independently represents hydrogen or a hydrocarbyl, such as alkyl, or any occurrence of Rix taken together with another and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • each expression e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • prodrug encompasses compounds that, under physiological conditions, are converted into therapeutically active agents.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • the invention relates to a compound of Formula I:
  • R 1 is H, alkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-O-alkyl, aryl, heteroaryl, or alkylene-CFy
  • R 2 is heterocyclyl
  • R 4 is H, or (Ci-Ce)-alkyl
  • R a is H, alkyl, cycloalkyl, CN, or -O-alkyl
  • R b is H, alkyl, aryl, heteroaryl, heterocylcyl, -O-cycloalkyl, -O-aryl, or -O- heterocyclyl;
  • R c is H, alkyl, cycloalkyl, hetrocyclyl, or alkylene-CF 3;
  • R d is aryl, heteroaryl, heterocyclyl, -O-cycloalkyl, -O-aryl, or -O- heterocyclyl;
  • R e is aryl, heteroaryl, or heterocyclyl
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is alkyl.
  • R 1 is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is alkylene-cycloalkyl.
  • alkylene- cycloalkyl is methylene-cyclopropyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is heterocyclyl. In some embodiments, R 1 is substituted heterocyclyl. In some embodiments, R 1 is N-containing heterocyclyl. In some embodiments, R 1 is substituted N-containing heterocyclyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is -alkylene-O-alkyl. In some embodiments, R 1 is methylene- O-methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 1 is aryl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is unsubstituted phenyl. In some embodiments, R 1 is substituted phenyl. In some embodiments, substituted phenyl is substituted with one or more substituents selected from alkyl and halogen.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is alkylene-CF3. In some embodiments, R 1 is methylene-CF3.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is heterocyclyl.
  • R 2 is substituted heterocyclyl.
  • R 2 is N-containing heterocyclyl.
  • the N-containing heterocyclyl is a 6- to l2-membered heterocyclyl.
  • R 2 is substituted with one or more substituents selected from amino, alkyl and alkoxy, wherein alkyl or alkoxy is substituted with morphilino, a cyclic amino, or an acyclic amino, and wherein said alkyl, alkoxy, morpholino, cyclic amino, or acyclic amino moiety is optionally substituted with one or more alkoxyls or fluorines.
  • R 2 is unsubstituted pyridinonyl. In certain embodiments, R 2 is substituted pyridinonyl. In some embodiments, substituted pyridinonyl is substituted with one or more substituents selected from alkyl, cycloalkyl, heterocycloalkyl, halogen, aryl, heteroaryl, and CF3.
  • R 2 is selected from
  • R 2 is selected from
  • the invention relates to any one of the aforementioned
  • the invention relates to any one of the aformentioned compounds, wherein R 4 is H.
  • the invention relates to any one of the aformentioned compounds, wherein R 4 is (Ci-C 6 )-alkyl.
  • R 4 is methyl, ethyl, iso- propyl, n-propyl, iso-butyl, n-butyl, or tert-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R a is H.
  • the invention relates to any one of the aforementioned compounds, wherein R a is alkyl. In some embodiments, R a is methyl.
  • the invention relates to any one of the aforementioned compounds, wherein R a is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is CN.
  • the invention relates to any one of the aforementioned compounds, wherein R a is -O-alkyl. In some embodiments, R a is -OMe.
  • the invention relates to any one of the aforementioned compounds, wherein R b is H.
  • the invention relates to any one of the aforementioned compounds, wherein R b is alkyl. In some embodiments, R b is methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R b is t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is aryl. In some embodiments, R b is substituted aryl.
  • the invention relates to any one of the aforementioned compounds, wherein R b is heteroaryl.
  • R b is substituted heteroaryl.
  • substituted aryl or substituted heteroaryl is substituted with one or more substituents selected from alkyl, halogen, OH, -O-alkyl, CN, cycloalkyl, or heterocycloalkyl.
  • R b is substituted aryl.
  • R b is selected from
  • the invention relates to any one of the aforementioned compounds, wherein R b is heterocylcyl.
  • R b is substituted heterocyclyl.
  • substituted heterocyclyl is substituted with one or more substituents selected from alkyl, OH, and -O-alkyl.
  • R b is
  • R b is selected from In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is -O-cycloalkyl. In some embodiments, R b is -O-cyclobutyl.
  • the invention relates to any one of the aforementioned compounds, wherein R b is -O-aryl. In some embodiments, R b is -O-phenyl.
  • the invention relates to any one of the aforementioned
  • the invention relates to any one of the aforementioned compounds, wherein R 3 is
  • the invention relates to any one of the aforementioned compounds, wherein R c is H.
  • the invention relates to any one of the aforementioned compounds, wherein R c is alkyl. In some embodiments, R c is methyl or ethyl.
  • the invention relates to any one of the aforementioned compounds, wherein R c is cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R c is heterocyclylakyl.
  • the invention relates to any one of the aforementioned compounds, wherein R c is halogen.
  • the invention relates to any one of the aforementioned compounds, wherein R c is CF 3.
  • the invention relates to any one of the aforementioned compounds, wherein R d is aryl.
  • R d is substituted aryl.
  • substituted aryl is substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylakyl, halogen, OH, OMe, CF 3 , and CN.
  • R d is selected from
  • the invention relates to any one of the aforementioned compounds, wherein R d is heterocyclyl. In some embodiments, R d is substituted heterocyclyl.
  • the invention relates to any one of the aforementioned compounds, wherein R d is heteroaryl.
  • R d is substituted heteroaryl.
  • substituted heterocyclyl or substituted heteroaryl is substituted with one or more substituents selected from alkyl and cycloalkyl.
  • the invention relates to any one of the aforementioned
  • the invention relates to any one of the aforementioned
  • the invention relates to any one of the aforementioned compounds, wherein R e is aryl. In some embodiments, R e is phenyl. In some embodiments, R e is substituted phenyl. In some embodiments, substituted phenyl is alkyl-substituted
  • the invention relates to any one of the aforementioned compounds, wherein R e is heteroaryl.
  • the invention relates to any one of the aforementioned compounds, wherein R e is heterocyclyl.
  • R e is substituted pyrrolidinyl. In some embodiments, R e is
  • alkyl substituted pyrrolidinyl In some embodiments,
  • the invention relates to any one of the aforementioned compounds, wherein the compound is a pharmaceutically acceptable salt.
  • the invention relates to a compound selected from the
  • the invention relates to a compound selected from the
  • the invention relates to a compound selected from the
  • the invention relates to a compound selected from the
  • the invention relates to a compound selected from the
  • the invention relates to a compound selected from the group In certain embodiments, the invention relates to a compound selected from the group.
  • the invention relates to a compound selected from the
  • the invention relates to a compound selected from the group consisting of: In certain embodiments, the invention relates to a compound selected from the
  • the invention relates to a compound selected from the group consisting In some embodiments, the invention relates to a compound selected from the group
  • the invention relates to a compound selected from the group
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the aforementioned compounds and a pharmaceutically acceptable carrier.
  • Patients including but not limited to humans, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable salt thereof in the presence of a pharmaceutically acceptable carrier or diluent.
  • the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, rectally, or topically, in liquid or solid form.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.
  • the mode of administration of the active compound is oral.
  • Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such
  • the compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup can contain, in addition to the active compound(s), sucrose or sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compound or a pharmaceutically acceptable salt thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatories or other antivirals, including but not limited to nucleoside compounds.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • carriers include physiological saline and phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems.
  • a controlled release formulation including but not limited to implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, poly orthoesters and polylactic acid.
  • enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.
  • Liposomal suspensions are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (incorporated by reference).
  • liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline
  • the invention relates to a method of treating a disease or condition selected from the group consisting of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, graft versus host disease, a chronic inflammatory disease of the lung, HIV, and hematological tumor, comprising the step of: administering to a subject in need thereof a therapeutically effective amount of any one of the aforementioned compounds.
  • a disease or condition selected from the group consisting of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangit
  • the disease or condition is inflammatory bowel disease.
  • the inflammatory bowel disease is colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteropathy associated with seronegative arthropathies, gastroenteritis, or pouchitis.
  • the disease or condition is colitis; and the colitis is ulcerative colitis, microscopic colitis, or collagenous colitis.
  • the disease or condition is pouchitis; and the pouchitis is the result of proctocolectomy.
  • the disease or condition is gastroenteritis.
  • the gastroenteritis is eosinophilic gastroenteritis.
  • the disease or condition is eosinophilic esophagitis.
  • the disease or condition is a chronic inflammatory disease of the lung.
  • the chronic inflammatory disease of the lung is interstitial fibrosis.
  • the intersititial fibrosis is hypersensitivity pneumonitis, collagen diseases, or sarcoidosis.
  • the disease or condition is a hematological tumor.
  • the hematological tumor is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma.
  • the invention relates to any one of the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is human.
  • the ester was treated with LiOH-FFO (7 equiv.) in MeOH FFO (3: 1 ratio) at room temperature for 2 hours.
  • the solvent was removed in vacuo, and the residue purified by preparatory HPLC conditions.
  • LC/MS A column: XBridge C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient: 5%-95% B in 1.4 min, then 1.6 min hold; flow rate: 1.8 mL/min; oven temperature 50 °C.
  • LC/MS B column: SunFire C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A water (0.01% TFA), B CH3CN; gradient: 5%-95% B in 1.5 min, then 1.5 min hold; flow rate: 2.0 mL/min; oven temperature 50 °C.
  • LC/MS C column: XBridge C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient: 5%-95%B in l.5min, then 1.5 min hold; flow rate: 1.8 mL/min; oven temperature 50 °C.
  • LC/MS D column: Poroshell 120 EC-C138, 4.6 X 30 mm, 2.7 pm; mobile phase: A water (0.01% TFA), B CftCN (0.01% TFA); gradient: 5%-95% B in 1.2 min, then 1.8 min hold; flow rate: 2.2 mL/min; oven temperature 50 °C.
  • Prep HPLC A column: XBridge C18, 21.2*250 mm, 10 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient elution as in text; flow rate: 20 mL/min.
  • Prep HPLC B column: XBridge C18, 21.2*250 mm, 10 pm; mobile phase: A water (10 mM formic acid), B CH3CN; gradient elution as in text; flow rate: 20 mL/min.
  • Racemic and/or diastereomeric products were separated to individual enantiomers by chiral Prep SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm:
  • Chiral SFC A column: (R,R)-Whelk-Ol, 4.6*l00mm, 5 pm (Decial), column temperature: 40 °C, mobile phase: CCk/methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g/min, back pressure: 120 bar.
  • Chiral SFC B column: AD 4.6*l00mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCk/methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g/min, back pressure: 120 bar.
  • Chiral SFC C column: AS 4.6*l00mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCk/methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g/min, back pressure: 120 bar.
  • Step 1 methyl 3-methoxy-2-(4-methyl-2-oxopyridin-l(2H)-yl)propanoate
  • Step 1 methyl 2-(5-methyl-2-oxopyridin-l(2H)-yl)-2-phenylacetate
  • Step 3 methyl (S)-3-amino-3-(3',5'-dimethyl-[3,4'-bipyridin]-5-yl)propanoate
  • Step 4 methyl (3S)-3-(3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-3-(4-methyl-2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 5 ((3S)-3-(3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-3-(4-methyl-2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoic acid
  • Step 1 (3S)-methyl 3-(5-(2, 6-dim ethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate
  • Step 2 (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoic acid
  • Step 2 (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2R)-4-methyl-2-(2-oxo- 4-(trifluoromethyl)piperidin-l-yl)pentanamido)propanoate
  • Step 1 (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2S)-4-methyl-2-(2-oxo- 4-(trifluoromethyl)piperidin-l-yl)pentanamido)propanoate
  • Step 1 (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(5-methyl-2- oxopyridin-l(2H)-yl)-2-phenylacetamido)propanoate
  • Step 2 (S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-2-(5-methyl-2-oxopyridin- l(2H)-yl)-2-phenylacetamido)propanoic acid & (S)-3-(5-(2,6-dimethylphenyl)pyridin- 3-yl)-3-((S)-2-(5-methyl-2-oxopyridin-l(2H)-yl)-2-phenylacetamido)propanoic acid
  • Step 3 (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2R)-2-(5-methyl-2- oxopiperidin-l-yl)-2-phenylacetamido)propanoic acid
  • Step 1 (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2S)-2-(5-methyl-2- oxopiperidin-l-yl)-2-phenylacetamido)propanoic acid
  • Step 2 3-(2 , ,6’-dimethylbiphenyl-3-yl)-3-(3-methoxy-2-(4-methyl-2-oxopyridin-l(2H)- yl)propanamido)propanoic acid
  • Methyl 3 -(2’ ,6’ -dimethylbiphenyl-3 -yl)-3 -(3 -methoxy-2-(4-methyl-2-oxopyridin- 1 (2H)- yl)propanamido)propanoate (150 mg, 0.32 mmol) was treated with L1OH-H2O (66 mg, 1.6 mmol) in THF (8 mL) and H2O (1 mL) at room temperature for 2 hours. Solvent was removed in vacuo and the residue was purified by Prep-HPLC B (30-70% MeCN) to give the compounds HI (10 mg) and H2 (30 mg) as white solids.
  • Step 1 (S)-methyl 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(2'- methylbiphenyl-3-yl)propanoate
  • Step 2 (S)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(2'- methylbiphenyl-3-yl)propanoic acid
  • Step 1 (S)-methyl 3-((R)-2-hydroxy-4-methylpentanamido)-3-(2'-methylbiphenyl-3- yl)propanoate
  • Step 1 (S)-methyl 3-(2',6'-difluorobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin- 3(4H)-yl)pentanamido)propanoate
  • Step 2 (S)-3-(2',6'-difluorobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)- yl)pentanamido)propanoic acid
  • Step 1 (S)-methyl 3-(3-bromophenyl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)- yl)pentanamido)propanoate
  • Step 2 (S)-methyl 3-(2'-cyanobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin- 3(4H)yl)pentanamido)propanoate
  • Step 3 (S)-3-(2'-cyanobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)- yl)pentanamido)propanoic acid
  • Step 2 (S)-3-(2'-fluoro-6'-methoxybiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin- 3(4H)-yl)pentanamido)propanoic acid
  • Step 1 (S)-methyl 3-(3-bromophenyl)-3-(tert-butoxycarbonylamino)propanoate
  • Step 2 (S)-methyl 3-(tert-butoxycarbonylamino)-3-(3-(piperidin-l-yl)phenyl) propanoate
  • Step 3 (S)-methyl 3-amino-3-(3-(piperidin-l-yl)phenyl)propanoate
  • Step 4 (S)-methyl 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(3- (piperidin-l-yl)phenyl)propanoate
  • Step 5 (S)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(3-(piperidin- l-yl)phenyl)propanoic acid
  • Step 41 methyl 3-(tert-butoxycarbonylamino)-3-(2-o-tolylpyridin-4-yl)propanoate B
  • Step 2 methyl 3-amino-3-(2-o-tolylpyridin-4-yl)propanoate
  • Step 3 methyl 3-(4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanamido)-3-(2-o- tolylpyridin-4-yl)propanoate
  • Step 4 3-(4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanamido)-3-(2-o-tolylpyridin-4- yl)propanoic acid
  • Step 3 3-(tert-butoxycarbonylamino)-3-(3-cyclobutoxyphenyl)propanoic acid
  • Step 4 benzyl 3-(tert-butoxycarbonylamino)-3-(3-cyclobutoxyphenyl)propanoate
  • Step 6 benzyl 3-(3-cyclobutoxyphenyl)-3-((S)-4-methyl-2-(2-oxopyridin-l(2H)- yl)pentanamido)propanoate
  • Step 4 (S)-methyl 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)phenyl)-3-((S)-4-methyl-2-(2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 4 3-amino-3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)propanoic acid
  • Step 5 methyl 3-amino-3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)propanoate
  • Step 6 methyl 3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)-3-((S)-4-methyl-2-(2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 7 3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin-l(2H)- yl)pentanamido)propanoic acid
  • Step 2 methyl 3-amino-3-(3-bromo-4-methylphenyl)propanoate
  • Step 3 methyl 3-amino-3-(2',6-dimethyl-[l,l'-biphenyl]-3-yl)propanoate
  • Step 4 methyl 3-(2',6-dimethyl-[l,l'-biphenyl]-3-yl)-3-(4-methyl-2-(2-oxopyridin- l(2H)-yl)pentanamido)propanoate
  • Step 5 3-(2',6-dimethyl-[l,l'-biphenyl]-3-yl)-3-(4-methyl-2-(2-oxopyridin-l(2H)- yl)pentanamido)propanoic acid
  • Step 2 3-(3-tert-butylphenyl)-3-(4-methyl-2-(2-oxopyridin-l(2H)- yl)pentanamido)propanoic acid
  • Step 2 3-(4-methyl-2-(2-oxopyridin-l(2H)-yl)pentanamido)-3-(3- phenoxyphenyl)propanoic acid
  • Step 2 methyl 3-amino-3-(5-bromopyridin-3-yl)propanoate
  • Step 4 methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopyridin- l(2H)-yl)pentanamido)propanoate
  • T2a The T2 mixture was further separated by Preparative chiral SFC D to give diastereomeric compounds T2a (8 mg) and T2b (7.5 mg) as white solids
  • Step 3 methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4,4,4-trifluoro-2-(2- oxopyridin-l(2H)-yl)butanamido)propanoate
  • Step 4 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4,4,4-trifluoro-2-(2-oxopyridin- l(2H)-yl)butanamido)propanoic acid
  • Step 3 methyl 3-(3-cyclopropyl-2-(2-oxopyridin-l(2H)-yl)propanamido)-3-(5-(2,6- dimethylphenyl)pyridin-3-yl)propanoate
  • Step 4 3-((S)-3-cyclopropyl-2-(2-oxopyridin-l(2H)-yl)propanamido)-3-(5-(2,6- dimethylphenyl)pyridin-3-yl)propanoic acid
  • Step 1 methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 2 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin- l(2H)-yl)pentanamido)propanoic acid
  • Step 1 methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin- 3-yl)propanoate
  • Step 2 methyl (S)-3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate
  • Step 3 methyl (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 4 (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoic acid
  • Step 1 (R)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,6-dimethylphenyl)pyridin-3- yl)propanoate
  • Step 3 (3R)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 4 (3R)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoic acid
  • Step 1 methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate
  • Step 2 methyl 3-(tert-butoxycarbonylamino)-3-(5-((S)-3-methylmorpholino) pyridin - 3-yl)propanoate
  • Step 3 methyl 3-amino-3-(5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate hydrochloride
  • Step 7 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(5-((S)-3- methylmorpholino)pyridin-3-yl)propanoic acid
  • Step 3 (3R)-methyl 3-(2-(4,5-dimethyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)- 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate
  • Step 4 (3R)-3-(2-(4,5-dimethyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)-3-(5- (2,6-dimethylphenyl)pyridin-3-yl)propanoic acid
  • Step 5 (3S)-methyl 3-(2-(4,5-dimethyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)- 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate
  • Step 6 (3S)-3-(2-(4,5-dimethyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)-3-(5- (2,6-dimethylphenyl)pyridin-3-yl)propanoic acid
  • Step 3 (S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-2-hydroxy-4- methylpentanamido)propanoate
  • Step 4 (S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-4-methyl-2- (methylsulfonyloxy)pentanamido)propanoate
  • Step 5 (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-iodo-4- methylpentanamido)propanoate
  • Step 6 (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(l-oxo-3,4- dihydroisoquinolin-2(lH)-yl)pentanamido)propanoic acid
  • Step 1 ethyl 4-methyl-2-(l-oxoisoindolin-2-yl)pentanoate
  • Step 3 (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(l- oxoisoindolin-2-yl)pentanamido)propanoate
  • Step 4 methyl 3-amino-3-(6-cyano-2'-methylbiphenyl-3-yl)propanoate
  • Step 5 methyl 3-(6-cyano-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin-l(2H)- yl)pentanamido)propanoate
  • Step 4 methyl 3-(6-methoxy-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin- l(2H)-yl)pentanamido)propanoate
  • Step 1 methyl 3-(3-bromo-4-methylphenyl)-3-((tert- butoxycarbonyl)amino)propanoate
  • Step 3 methyl 3-amino-3-(4-methyl-3-morpholinophenyl)propanoate hydrochloride
  • Step 4 4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(4-methyl-3- morpholinophenyl)propanoate
  • Step 5 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(4-methyl-3- morpholinophenyl)propanoic acid
  • Step 6 methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-l(2H)-yl)pentanamido)-3-(6- methyl-5-o-tolylpyridin-3-yl)propanoate
  • Step 5 Compounds AE1 and AE2
  • Step 8 methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-l(2H)-yl)pentanamido)-3-(6- methyl-5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate
  • Step 1 (S)-methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate
  • Step 3 (3S)-methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-l(2H)-yl)pentanamido)-3- (5-((S)-2-methylpiperidin-l-yl)pyridin-3-yl)propanoate
  • Step 4 (S)-3-((S)-4-methyl-2-(4-methyl-2-oxopyridin-l(2H)-yl)pentanamido)-3-(5-((S)- 2-methylpiperidin-l-yl)pyridin-3-yl)propanoic acid
  • Step 1 (R)-methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate
  • Step 2 (R)-methyl 3-amino-3-(5-((S)-2-methylpiperidin-l-yl)pyridin-3-yl)propanoate
  • Step 3 methyl (3R)-3-(4-methyl-2-(4-methyl-2-oxopyridin-l(2H)-yl)pentanamido)-3- (5-((S)-2-methylpiperidin-l-yl)pyridin-3-yl)propanoate
  • Step 4 (3R)-3-(4-methyl-2-(4-methyl-2-oxopyridin-l(2H)-yl)pentanamido)-3-(5-((S)-2- methylpiperidin-l-yl)pyridin-3-yl)propanoic acid
  • Step 1 (R)-benzyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate hydrochloride
  • Step 2 (3R)-benzyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 3 (3R)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopiperidin-l- yl)pentanamido)propanoic acid
  • Step 3 methyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate
  • Step 4 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoic acid
  • Step 6 benzyl 3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin-3- yl)propanoate
  • Step 8 (3S)-benzyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 9 (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopiperidin-l- yl)pentanamido)propanoic acid
  • Step 3 methyl (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(4-methyl-2- oxopyridin-l(2H)-yl)pentanamido)propanoate
  • Step 4 (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(4-methyl-2-oxopyridin- l(2H)-yl)pentanamido)propanoic acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne des antagonistes à petites molécules de l'intégrine α4β7, et des procédés d'utilisation de ceux-ci pour traiter un certain nombre de maladies ou d'états spécifiques.
PCT/US2019/027141 2018-04-12 2019-04-12 Antagonistes de l'intégrine humaine (alpha4) (beta7) WO2019200202A1 (fr)

Priority Applications (4)

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JP2020555323A JP7365358B2 (ja) 2018-04-12 2019-04-12 ヒトインテグリンα４β７のアンタゴニスト
CN201980033206.5A CN112312910A (zh) 2018-04-12 2019-04-12 人整合素α4β7拮抗剂
EP19785592.7A EP3773573A4 (fr) 2018-04-12 2019-04-12 Antagonistes de l'intégrine humaine (alpha4) (beta7)
JP2023174330A JP2024001201A (ja) 2018-04-12 2023-10-06 ヒトインテグリンα４β７のアンタゴニスト

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US62/656,742 2018-04-12

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MA (1) MA52249A (fr)
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10759756B2 (en) 2018-04-12 2020-09-01 Morphic Therapeutic, Inc. Antagonists of human integrin α4β7
WO2021076902A1 (fr) * 2019-10-16 2021-04-22 Morphic Therapeutic, Inc. INHIBITION DE L'INTÉGRINE α 4 β 7 HUMAINE
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin
TWI840047B (zh) 2020-10-16 2024-04-21 美商莫菲克醫療股份有限公司 人類整合素α4β7之抑制

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023125182A1 (fr) * 2021-12-27 2023-07-06 海思科医药集团股份有限公司 Dérivé d'acide propionique et son utilisation médicale
WO2024051819A1 (fr) * 2022-09-09 2024-03-14 西藏海思科制药有限公司 Dérivé d'acide propionique et son utilisation en médecine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5981492A (en) * 1993-11-15 1999-11-09 Hoechst Aktiengesellschaft Substituted 5-membered ring heterocycles, their preparation and their use
US6294562B1 (en) * 1996-06-05 2001-09-25 Hoechst Aktiengesellschaft Salts of ethyl 3-(2-(4-(4-amino-imino-methyl)phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)acetylamino)-3-phenylpropionate
US6723711B2 (en) * 1999-05-07 2004-04-20 Texas Biotechnology Corporation Propanoic acid derivatives that inhibit the binding of integrins to their receptors

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100257837B1 (ko) * 1993-03-31 2000-07-01 윌리암스 로저 에이 혈소판응집 저해제로서의 1-아미디노페닐-피롤리돈 피페리딘온 아제틴온
EP0730590B1 (fr) * 1993-11-24 2001-01-17 Dupont Pharmaceuticals Company antagonistes de recepteur de fibrinogene, a base d'isoxazoline et d'isoxazole
US5849736A (en) * 1993-11-24 1998-12-15 The Dupont Merck Pharmaceutical Company Isoxazoline and isoxazole fibrinogen receptor antagonists
US5981546A (en) * 1996-08-29 1999-11-09 Merck & Co., Inc. Integrin antagonists
CA2268270A1 (fr) 1996-10-11 1998-04-23 Cor Therapeutics, Inc. Derives heterocycliques utilises comme inhibiteurs de facteur xa
EP0932615A1 (fr) 1996-10-11 1999-08-04 Cor Therapeutics, Inc. INHIBITEURS SELECTIFS DU FACTEUR Xa
DE19751251A1 (de) * 1997-11-19 1999-05-20 Hoechst Marion Roussel De Gmbh Substituierte Imidazolidinderivate, ihre Herstellung, ihre Verwendung und sie enthaltende pharmezeutische Präparate
US6645939B1 (en) 1997-11-24 2003-11-11 Merck & Co., Inc. Substituted β-alanine derivatives as cell adhesion inhibitors
MY153569A (en) 1998-01-20 2015-02-27 Mitsubishi Tanabe Pharma Corp Inhibitors of ?4 mediated cell adhesion
DE19821483A1 (de) * 1998-05-14 1999-11-18 Hoechst Marion Roussel De Gmbh Imidazolidinderivate, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate
EP1091945A1 (fr) * 1998-06-29 2001-04-18 Du Pont Pharmaceuticals Company Isoxazolidines et carbamates cycliques utilises comme antagonistes de iib/iiia
GB9826174D0 (en) * 1998-11-30 1999-01-20 Celltech Therapeutics Ltd Chemical compounds
KR100767199B1 (ko) 1999-05-07 2007-10-17 엔싸이시브 파마슈티칼즈 인코퍼레이티드 인테그린이 이의 수용체에 결합하는 것을 억제하는프로판산 유도체
US6972296B2 (en) 1999-05-07 2005-12-06 Encysive Pharmaceuticals Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
WO2001021584A1 (fr) 1999-09-24 2001-03-29 Genentech, Inc. Derives de tyrosine
DE10041423A1 (de) 2000-08-23 2002-03-07 Merck Patent Gmbh Biphenylderivate
DE10111876A1 (de) * 2001-03-10 2002-09-19 Aventis Pharma Gmbh Bis(trifluormethyl)hydantoine als Zwischenprodukte für pharmazeutische Wirkstoffe
DE10154280A1 (de) 2001-11-05 2003-05-15 Wilex Ag Antagonisten für alpha¶4¶-Integrine
MXPA04008267A (es) 2002-02-25 2004-11-10 Elan Pharm Inc Administracion de agentes para el tratamiento de la inflamacion.
PT2990422T (pt) 2004-09-03 2018-10-18 Genentech Inc Antagonistas humanizados anti-beta7 e suas utilizações
EP1863940B1 (fr) 2005-03-03 2012-06-06 Seedlings Life Science Ventures, LLC. Méthode de gestion des risques concernant les patients soumis à un traitement à base de natalizumab
WO2006126529A1 (fr) 2005-05-25 2006-11-30 Shionogi & Co., Ltd. Derive de morphinane substitue en position 7 par un carbamoyle et insature en positions 6 et 7
DE602006019731D1 (de) 2005-06-09 2011-03-03 Ucb Pharma Sa 2,6-chinolinderivate sowie verfahren zu ihrer herstellung und verwendung als arzneimittel
LT2676967T (lt) 2006-02-28 2019-09-10 Biogen Ma Inc. Uždegiminių ir autoimuninių ligų gydymo būdai su natalizumabu
WO2010091411A1 (fr) 2009-02-09 2010-08-12 Glaxosmithkline Llc Agents antiviraux à base de pipéridinyle amido cyclique
CN109734807A (zh) 2011-03-31 2019-05-10 豪夫迈·罗氏有限公司 施用β7整联蛋白拮抗剂的方法
SG11201502548YA (en) 2012-10-05 2015-04-29 Genentech Inc Methods for diagnosing and treating inflammatory bowel disease
MX2016012282A (es) 2014-03-27 2017-01-06 Genentech Inc Metodos para diagnosticar y tratar enfermedad inflamatoria de intestino.
WO2016011940A1 (fr) 2014-07-25 2016-01-28 江苏恒瑞医药股份有限公司 Dérivé d'indole-amide, son procédé de préparation et son application en médecine
KR20170120601A (ko) 2015-02-26 2017-10-31 제넨테크, 인크. 인테그린 베타7 길항제 및 크론병을 치료하는 방법
US10246451B2 (en) 2017-04-26 2019-04-02 Aviara Pharmaceuticals, Inc. Propionic acid derivatives and methods of use thereof
AR114489A1 (es) * 2018-04-12 2020-09-09 Morphic Therapeutic Inc ANTAGONISTAS DE LA INTEGRINA a4b7 HUMANA
EP3873884A1 (fr) 2018-10-30 2021-09-08 Gilead Sciences, Inc. Dérivés de quinoléine utilisés en tant qu'inhibiteurs de l'intégrine alpha4bêta7
WO2020092401A1 (fr) 2018-10-30 2020-05-07 Gilead Sciences, Inc. COMPOSÉS POUR INHIBITION DE L'INTÉGRINE ALPHA 4β7
KR102641718B1 (ko) 2018-10-30 2024-02-29 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린 억제제로서의 이미다조피리딘 유도체
JP7189368B2 (ja) 2018-10-30 2022-12-13 ギリアード サイエンシーズ， インコーポレイテッド アルファ４ベータ７インテグリンの阻害のための化合物
JP7437490B2 (ja) 2019-10-16 2024-02-22 モーフィック セラピューティック，インコーポレイテッド ヒトインテグリン（アルファ－４）（ベータ－７）の阻害

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5981492A (en) * 1993-11-15 1999-11-09 Hoechst Aktiengesellschaft Substituted 5-membered ring heterocycles, their preparation and their use
US6294562B1 (en) * 1996-06-05 2001-09-25 Hoechst Aktiengesellschaft Salts of ethyl 3-(2-(4-(4-amino-imino-methyl)phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)acetylamino)-3-phenylpropionate
US6723711B2 (en) * 1999-05-07 2004-04-20 Texas Biotechnology Corporation Propanoic acid derivatives that inhibit the binding of integrins to their receptors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics", 1986
BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
See also references of EP3773573A4
STILZ ET AL.: "Discovery of an Orally Active Non-Peptide Fibrinogen Receptor Antagonist", J. MED. CHEM., vol. 39, 1996, pages 2118 - 2122, XP000578006, DOI: 10.1021/jm960210f *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)
US10759756B2 (en) 2018-04-12 2020-09-01 Morphic Therapeutic, Inc. Antagonists of human integrin α4β7
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
WO2021076902A1 (fr) * 2019-10-16 2021-04-22 Morphic Therapeutic, Inc. INHIBITION DE L'INTÉGRINE α 4 β 7 HUMAINE
US11370773B1 (en) 2019-10-16 2022-06-28 Morphic Therapeutic, Inc. Inhibiting human integrin (alpha-4) (beta-7)
JP2022548809A (ja) * 2019-10-16 2022-11-22 モーフィック セラピューティック，インコーポレイテッド ヒトインテグリンα４β７の阻害
JP7209116B2 (ja) 2019-10-16 2023-01-19 モーフィック セラピューティック，インコーポレイテッド ヒトインテグリンα４β７の阻害
TWI791304B (zh) * 2019-10-16 2023-02-01 美商莫菲克醫療股份有限公司 人類整合素α4β7之抑制
EP4045039A4 (fr) * 2019-10-16 2023-12-13 Morphic Therapeutic, Inc. Inhibition de l'intégrine humaine alpha4beta7
TWI840047B (zh) 2020-10-16 2024-04-21 美商莫菲克醫療股份有限公司 人類整合素α4β7之抑制

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US20190315692A1 (en) 2019-10-17
US20200385352A1 (en) 2020-12-10
CN112312910A (zh) 2021-02-02
MA52249A (fr) 2021-05-05
TW202003466A (zh) 2020-01-16
AR114489A1 (es) 2020-09-09
EP3773573A1 (fr) 2021-02-17
US11174228B2 (en) 2021-11-16
JP2021531234A (ja) 2021-11-18
EP3773573A4 (fr) 2022-04-06
JP7365358B2 (ja) 2023-10-19
US20220340529A1 (en) 2022-10-27

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